| First Author | Chen YS | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 33 | Pages | E3061-70 |
| PubMed ID | 23901118 | Mgi Jnum | J:200682 |
| Mgi Id | MGI:5509083 | Doi | 10.1073/pnas.1300860110 |
| Citation | Chen YS, et al. (2013) Microsatellite-encoded domain in rodent Sry functions as a genetic capacitor to enable the rapid evolution of biological novelty. Proc Natl Acad Sci U S A 110(33):E3061-70 |
| abstractText | The male program of therian mammals is determined by Sry, a transcription factor encoded by the Y chromosome. Specific DNA binding is mediated by a high mobility group (HMG) box. Expression of Sry in the gonadal ridge activates a Sox9-dependent gene regulatory network leading to testis formation. A subset of Sry alleles in superfamily Muroidea (order Rodentia) is remarkable for insertion of an unstable DNA microsatellite, most commonly encoding (as in mice) a CAG repeat-associated glutamine-rich domain. We provide evidence, based on an embryonic pre-Sertoli cell line, that this domain functions at a threshold length as a genetic capacitor to facilitate accumulation of variation elsewhere in the protein, including the HMG box. The glutamine-rich domain compensates for otherwise deleterious substitutions in the box and absence of nonbox phosphorylation sites to ensure occupancy of DNA target sites. Such compensation enables activation of a male transcriptional program despite perturbations to the box. Whereas human SRY requires nucleocytoplasmic shuttling and coupled phosphorylation, mouse Sry contains a defective nuclear export signal analogous to a variant human SRY associated with inherited sex reversal. We propose that the rodent glutamine-rich domain has (i) fostered accumulation of cryptic intragenic variation and (ii) enabled unmasking of such variation due to DNA replicative slippage. This model highlights genomic contingency as a source of protein novelty at the edge of developmental ambiguity and may underlie emergence of non-Sry-dependent sex determination in the radiation of Muroidea. |
